1. Field of the Invention
This invention relates to novel FK520 and FK506 analogs and other similar calcineurin inhibitors, methods for making these analogs, and their use for treating immunoregulatory and respiratory diseases, disorders, and conditions.
2. Description of the State of the Art
FK520, originally called ascomycin, is a substantial component of a large family of macrocyclic fermentation products. This family, originally isolated from cultures of Streptomyces hygroscopicus var. ascomyceticus (T. Arai, et al., J. Antibiotics (Tokyo) 15 (Ser. A), 231-232 (1962)), is produced as a group of secondary fungal metabolites. Ascomycin was initially pursued for its antifungal activities but it is also an effective immunosuppressant, acting primarily through T-lymphocytes via inhibition of the phosphatase calcineurin. Ascomycin reduces the production of a range of cytokines, inhibiting the activation of various cell types, including those involved in cell-mediated immunity. Due to these properties, ascomycin remains an interesting substrate for development of therapeutics in the transplantation field. This molecule is a close chemical analog of FK506 (tacrolimus), which is currently utilized as a first-line therapy for transplantation rejection.
In addition to its wide use to prevent and treat organ transplant rejection, the FK family of molecules has been evaluated in a large range of disorders linked to immunoregulatory dysfunction and respiratory diseases. FK506, along with other calcineurin inhibitors (for example, cyclosporin A), has been used for the treatment of nephritic syndrome, active Crohn's disease, acute ocular Behcet syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, aplastic anemia, primary biliary cirrhosis, celiac disease and other immunoregulatory diseases. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyostitis/dermatomyositis or severe corticosteroid-dependent asthma (D. Faulds, et al., Drug Evaluation, 45:953 (1993) and P. J. Wahab, et. al., Aliment Pharmacol Ther., 14:767 (2000)). Other immunosuppressants (e.g., FK520 analogs, for example Elidel) are effective for these disease states. The effect of FK506 and other calcineurin inhibitors (e.g., FK520 analogs, cyclosporin) on inflammatory cells and their mediators make it a promising therapy for asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and other lung diseases. Treatment of these disorders with potent immunosuppressants such as cyclosporin or FK506 is currently limited to patients with severe disease that are either refractory or hypersensitive to standard treatments. This limitation is due to adverse events of treatment, including, but not limited to, hypertrichosis, gingival hyperplasia, neurological effects, gastrointestinal effects, and renal dysfunction. Chronic treatment with calcineurin inhibitors requires frequent renal function monitoring due to increased incidence of kidney failure.

The mechanism of toxicity of unmodified calcineurin inhibitors such as FK520, FK506 and cyclosporin has been related to the mechanism of immunosuppression (F. J. Dumont, et al., J. Exp. Med., 176:751-760 (1992). This strong link between the mechanism of action and the many macrocyclic-induced toxicities has presented a significant challenge to improving the therapeutic index of FK506, FK520 and cyclosporin through chemical modification. Indeed, efforts to date have failed to separate the efficacy of these molecules from their systemic toxicities. Segregation of efficacy and toxicity of new analogs might still be possible by altering a compound's distribution or metabolism (N. H. Signal, et. al., J. Exp. Med., 173:619 (1991)). By limiting the exposure and potential toxicity of an active calcineurin inhibitor to organs that are sensitive to such inhibition (e.g., kidney), system toxicity can be avoided. At the same time, the topical exposure of the active calcineurin inhibitor at a required site of action in diseased tissues and organs (skin, lung, gut, eye, etc.) can be maximized.